Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients

We tested the hypothesis that glucose intolerance develops in genetically prone subjects when exogenous insulin resistance is induced by dexamethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of beta-cell function alone and/or insulin resistance. Oral glucose tolerance (OGTT) and intravenous glucose tolerance tests with minimal model analysis were performed before and following 5 days of dex treatment (4 mg/day) in 20 relatives of non-insulin-dependent diabetic (NIDDM) patients and in 20 matched control subjects (age: 29.6 +/- 1.7 vs 29.6 +/- 1.6 years, BMI: 25.1 +/- 1.0 vs 25.1 +/- 0.9 kg/m(2)). Before dex, glucose tolerance was similar in both groups (2-h plasma glucose concentration (PG): 5.5 +/- 0.2 [range: 3.2-7.0] vs 5.5 +/- 0.2 [3.7-7.4] mmol/ 1). Although insulin sensitivity (Si) was significantly lower in the relatives before dex, insulin sensitivity was reduced to a similar level during dex in both the relatives and control subjects (0.30 +/- 0.04 vs 0.34 +/- 0.04 10(-4) min(-1) per pmol/l, NS). During dex, the variation in the OGTT 2-h PG was greater in the relatives (8.5 +/- 0.7 [3.9-17.0] vs 7.5 +/- 0.3 [5.7-9.8] mmol/l, F-test p < 0.05) which, by inspection of the data, was caused by seven relatives with a higher PG than the maximal value seen in the control subjects (9.8 mmol/l). These ''hyperglycaemic'' relatives had diminished first phase insulin secretion (empty setl) both before and during dex compared with the ''normal'' relatives and the control subjects (pre-dex empty set1: 12.6 +/- 3.6 vs 26.4 +/- 4.2 and 24.6 +/- 3.6 (p < 0.05), post-dex empty set1: 22.2 +/- 6.6vs 48.0 +/- 7.2 and 46.2 +/- 6.6 respectively (p < 0.05) pmol.l(-1).min(-1) per mg/dl). However, Si was similar in ''hyperglycaemic'' and ''normal'' relatives before dex (0.65 +/- 0.10 vs 0.54 +/- 0.10 10(-4).min(-1) per pmol/l) and suppressed similarly during dex (0.30 +/- 0.07 vs 0.30 +/- 0.06 10(-4) min(-1) per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent development of high 2-h post-dex OGTT plasma glucose levels (R-2 = 0.56). In conclusion, exogenous induced insulin resistance by dex will induce impaired or diabetic glucose tolerance in those genetic relatives of NIDDM patients who have impaired beta-cell function (retrospectively) prior to dex exposure. These subjects are therefore unable to enhance their beta-cell response in order to match the dex-induced insulin resistant state.